Hypertension

Systemic hypertension (2016)

SA Brown, Athens, USA

Target-organ damage to the kidney

Systemic hypertension is of concern because a chronically sustained increase in blood pressure (BP) produces injury to the kidneys, eyes, brain, and cardiovascular system. The rationale for treating hypertension in dogs and cats is to minimize or prevent this injury to these organs. Damage that results from the presence of sustained high BP is referred to as end-organ or target-organ damage (TOD). In the kidney, TOD is generally manifest as an enhanced rate of decline of renal function, mortality, increased frequency of uremic crises, and/or increased magnitude of proteinuria. Hypertension may be present in any IRIS (International Renal Interest Society) stage of chronic kidney disease (CKD) or grade of acute kidney injury, as blood creatinine concentration is not directly correlated to BP. Many dogs and cats with hypertension have ocular, CNS, and/or cardiovascular TOD. Effective treatment generally reduces the likelihood of further TOD in these tissues.

Measurement of systemic arterial blood pressure (BP)

Diagnosis and management of hypertension in dogs and cats with acute or chronic kidney disease should be based on measurement of the patient's BP. The choice of measurement device depends on operator experience and preference, although many veterinarians prefer Doppler devices for cats. The cuff width should be 30–40% of the circumference of the measurement site, which may be the tail, antebrachium, tarsus, or brachium. At least five measurements should be taken. The readings giving the highest and lowest value for systolic BP should be discarded with the final result determined as the average of the remaining three or more values, as long as all systolic BP results are within 20 mm Hg of each other. If the remaining systolic BP readings differ by more than 20 mm Hg, the measurement session should be repeated. Results of all BP measurements, rationale for excluding values, the final (mean) result, and interpretation of the result by the veterinarian should be recorded. The animal's position and attitude, cuff size and site, cuff site circumference (cm), and the BP values obtained should be carefully considered and noted in the animal's record. It is customary to conduct at least two measurement sessions, normally separated by at least one week, before concluding that an animal is in need of antihypertensive therapy.

Interpretation of BP

Approximately 20% of animals with chronic kidney disease (CKD) are hypertensive at the time of initial diagnosis and an additional 10-20% of initially normotensive animals will become hypertensive over time. The IRIS recommendation is that BP should be measured, and CKD substage will be determined using the criteria shown in Table 1. Similar classification using BP should be undertaken in animals with acute kidney injury or in those suspected of having systemic hypertension due to other underlying diseases..  
 

Table 1: IRIS substaging of blood pressure (BP) fin dogs and cats based on risk for future target-organ damage*

Systolic blood pressure (mm Hg)Diastolic blood pressure (mm Hg)Risk of future target organ damageBP substage
OriginalNew
<150 <95 Minimal AP0 Normotensive
150 - 159 95 - 99 Mild AP1 Borderline hypertensive
160 - 179 100 - 119 Moderate AP2 Hypertensive
≥180 ≥120 Severe AP3 Severely hypertensive

Note: systolic blood pressures are used for IRIS CKD substaging (the diastolic values here are only informative)

Treatment

The initial assessment of an animal suspected to have systemic hypertension should include recognizing conditions that may be contributing to an increase in BP, identifying and characterizing TOD, and determining if there are any seemingly unrelated, concurrent conditions that may complicate antihypertensive therapy. Because hypertension is often a silent, slowly progressive condition requiring vigilance and life-long therapy, it is important to be absolutely certain about the diagnosis: a high BP measurement in a dog or cat with CKD could represent artifactual (anxiety-induced or "white-coat") hypertension. White-coat hypertension is not an indication for treatment. A decision to use antihypertensive drugs should be based on the BP substage (Table 1) and integration of all clinically available information.

Decision to institute treatment

In people, any reduction of BP that does not produce overt hypotension lowers the risk of TOD. This finding remains to be confirmed in dogs and cats but IRIS recommends that BP be categorized on the basis of risk of future TOD. Although interbreed differences in BP exist in dogs, only the difference for Sight Hounds (20 mm Hg higher values for each category) mandates separate categorization at present.

 

The general consensus is to institute therapy in a patient with evidence of TOD, if reliable measurements of BP indicate that systolic BP (BP) exceeds 160 mm Hg (that is, for hypertensive and severely hypertensive patients - see Table 1) and in a patient with persistent hypertension. Animals with CKD are presumed to have TOD, even though it may not be clinically apparent.

Antihypertensive therapy

Antihypertensive therapy must be individualized to the patient and its concurrent conditions. Regardless of the initial BP, the optimal goal of therapy should be to reduce the risk of future TOD to minimal (systolic BP<150). Some patients exhibit extreme elevations of BP and reduction of systolic BP may be difficult. In these patients, an alternate goal is to reduce the risk for TOD by at least one substage (Table 1). In most circumstances BP lowering should be achieved with a gradual, persistent reduction of BP achieved over several weeks. The presence of severe CNS or ocular TOD justifies emergency management as a hypertensive crisis, with rapid lowering of BP over several hours. Unfortunately, severe ocular damage (e.g., retinal detachment or marked intraocular haemorrhage) is usually associated with chronic retinal injury such that the animal may remain blind even if the antihypertensive regimen is effective.

While available evidence suggests sodium restriction alone generally does not reduce BP, high salt intake may produce adverse consequences in some settings. Normal dogs and cats are apparently not as salt-sensitive as people or some inbred strains of rats, but it is likely that those with kidney diseases, especially the nephrotic syndrome, are salt sensitive. Furthermore, salt restriction enhances the antihypertensive efficacy of some antihypertensive agents, particularly those that interfere with the renin-angiotensin-aldosterone system (RAAS). This evidence from laboratory studies of dogs and cats serves as the basis for the recommendation to feed a diet with reduced sodium chloride content to dogs and cats with CKD, regardless of IRIS stage.

In dogs with systemic hypertension, the initial therapeutic choice is often a drug that interferes with the RAAS, specifically angiotensin-converting enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARBs). Clinical experience indicates that both classes of RAAS blockers reduce BP slightly (~ 10–15%) and are antiproteinuric. The starting dosage should be adjusted to the individual patient based on the recommended range (Table 2). Caution should be exercised in azotemic animals when dosage adjustments are made.

 

Table 2: Oral agents for antihypertensive therapy for dogs (D) and cats (C)


Note: some of the treatment recommendations are not authorised for use in all geographical regions and some may not be authorised for use in dogs and/or cats. Such recommended dose rates are therefore empirical. It is the treating veterinarian’s duty to make a risk:benefit assessment for each patient prior to administering any treatment.
ClassDrugUsual oral dosage
ACEI /ARB:
Angiotensin converting
enzyme inhibitor
Benazepril D: 0.5-2.0 mg/kg q 12 h
C: 0.5-2.0 mg/kg q 24 h
Enalapril D: 0.5-2.0 mg/kg q 12 h
C: 0.5-2.0 mg/kg q 24 h
Ramipril D/C: 0.25-1.0 mg/kg q 24 h
Imidapril D/C: 0.25-1.0 mg/kg q 24 h
Angiotensin receptor blocker Losartan D: 0,5-1,0 mg/kg q 24 h
Irbesartan D: 1-5 mg/kg q 12-24 h
CCB:
Calcium channel blocker Amlodipine D/C: 0.1-0.75 mg/kg q 24 h
OTHER AGENTS:
β blocker Atenolol D: 0.25-1.0 mg/kg q 12 h
C: 6.25-12.5 mg/cat q 12 h
Aldosterone antagonist Spironolactone D/C: 1.0-2.0 mg/kg q 12-24 h
α blocker Prazosin D: 0.5-2 mg/kg q 8-12 h
C: 0.25-0.5 mg/cat q 24 h
Phenoxybenzamine D: 0.25 mg/kg q 8-12 h
or 0.5 mg/kg q 24 h
C: 2.5 mg/cat q 8-12 h
or 5 mg/cat q 24 h
Direct vasodilator Hydralazine D: 0.5-2 mg/kg q 12 h
(start at low end of range)
C: 2.5 mg/cat q 12-24 h
Acepromazine D/C: 0.5-2 mg/kg q 8 h
DIURETICS:
Thiazide diuretic Hydrochlorothiazide D/C: 2-4 mg/kg q 12-24 h
Loop diuretic Furosemide D/C: 1-4 mg/kg q 8-24 h

If an antihypertensive agent of choice is only partially effective, the usual approach is to increase the dosage before adding another drug. Thus, if a dog with CKD receiving an ACEi or an ARB remains hypertensive or severely hypertensive, upward adjustment of the dosage should be the first consideration. Many veterinarians start RAAS inhibitors at the lower limit of the recommended dosage (Table 2) and many experts will increase the ACEi dosage further, up to 2.0 mg/kg. Increasing an RAAS inhibitor beyond the suggested dosage range is not recommended. If an ACEi and/or an ARB is/are given at the upper end of the dosage range/s but the response is inadequate, some will co-administer an ACEi and an ARB, but there are no published reports of the efficacy or safety of this approach. More typically, the next step is to add a CCB to RAAS inhibition, typically 0.25–0.50 mg amlodipine/kg once daily. The CCB dosage may be increased to 0.75 mg/kg once daily. While not ideal, some hypertensive dogs with significant hypertension will require more than two agents. There is no consensus as to which agent (ARB, sympatholytic, or direct vasodilator) to add next. In fact, certain disease conditions may be best addressed by adding specific classes of agents to the ACEi/ARB/CCB combination, such as alpha- and beta-blockers or surgical excision for pheochromocytoma; or for hypertension associated with hyperaldosteronism, either an aldosterone receptor blocker or surgical excision of the adrenal tumor. Diuretics are rarely used as antihypertensives in dogs and cats, but may be useful in patients with concurrent hypertension and chronic overhydration.

In cats with systemic hypertension, the principles are as above, though the initial therapeutic choice should be a CCB, specifically amlodipine. Second choice agents, particularly in proteinuric cats, would be drugs that interfere with the RAAS, specifically an ACEi or an ARB. Agent of these classes (i.e., CCB and ACEi, CCB and ARB) can be co-administered.

An exception to the above gradual approach, where substantial time (weeks) is allowed between dosage adjustment, is animals classed as severely hypertensive with evidence of severe or progressing neural or ocular TOD. This generally constitutes an emergency, where combination therapy with a RAAS inhibitor plus a CCB is an appropriate first step in dogs, and a CCB will often be used alone in cats. When mentation is compromised, injectable or rectally administered medications should be initially used. The goal in either species is to reduce BP within hours, adjusting dosages within that time frame as necessary.

The benefit of lowering blood pressure on TOD within the kidney (where the damage is evident as a progressive decline in glomerular filtration rate) is directly dependent on the degree of proteinuria in people and cats, and there is presumably a similar relationship in proteinuric dogs. Thus monitoring of the urine protein-to-creatinine ratio is important, with the goal of reducing it to the non-proteinuric range (Table 3) or by 50% or more. The CCB in common use (amlodipine) may be less antiproteinuric than RAAS inhibitors due to preferential dilation of the afferent arteriole. However, CCB often are anti-proteinuric in cats.

 

Table 3: IRIS substaging of persistent renal proteinuria based on urine protein-to-creatinine ratio (UP/C, in mass units) in cats and dogs

Cats
(UP/C)
Dogs
(UP/C)
Proteinuria
substage
<0.2 <0.2 Nonproteinuric (NP)
0.2-0.4 0.2-0.5 Borderline Proteinuria (BP)
>0.4 >0.5 Proteinuric (P)

Monitoring antihypertensive therapy

Evident ocular and/or neural TOD constitute a hypertensive crisis, necessitating rapid lowering of BP. In most other situations, hypertension is not an emergency and 3–4 weeks should be allowed between dosage adjustments. There has been some concern about acute exacerbation of azotemia with RAAS inhibition, though this is unusual and modest increases in blood creatinine concentration (<30%) are generally tolerable. Nonetheless, a dog in IRIS Stage 1 or 2 should be evaluated 3–14 days after any change in antihypertensive therapy and this evaluation should include clinical assessment and measurement of blood creatinine, BP and the UP/C. In unstable patients and those with IRIS Stage 3 or 4, this recheck should be conducted earlier, perhaps within 3–5 days. Patients deemed to be hypertensive emergencies and hospitalized patients, particularly those receiving fluid therapy or pharmacological agents with cardiovascular effects, should be assessed (clinical evaluation and assessment of blood creatinine and BP) at least daily. The purpose of these short-term assessments is to identify findings that are unexpected (e.g., new or worsening TOD) or adverse (e.g., marked worsening of azotemia or systemic hypotension). Clinical findings of weakness or syncope with BP <120/60 mm Hg indicates systemic hypotension and therapy should be adjusted accordingly.

Re-evaluation is appropriate at 1–4 month intervals, depending on stability (more frequent if BP or other conditions are unstable) and degree of hypertension (more frequent if BP remains >180 mm Hg). Follow-up evaluations to assess efficacy and adjust therapy should include assessment of BP, blood creatinine concentration, urinalysis with quantitative assessment of proteinuria, funduscopic examination, and any other specific evaluations depending on circumstances (e.g., TOD, causes of secondary hypertension, concurrent conditions) of the patient. A key predictive indicator of antihypertensive efficacy is its effect on proteinuria: a benefit is predicted if the antihypertensive regimen is antiproteinuric (e.g., reduces urine protein/creatinine by >50%). The frequency and nature of re-evaluations will vary depending on the BP substage, stability of BP, other aspects of the health of the patient, and frequency of dosage adjustment to antihypertensive therapy. Since signs of progression of TOD can be subtle, BP should be closely monitored over time in patients receiving antihypertensive therapy, even when hypertension is seemingly well-controlled.

Additional reading

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